Nonlinear Optical Staging of Epithelial Neoplasms

描述（由申请人提供）：拟议研究的长期目标是利用多光子显微镜（MPM）和二次谐波产生显微镜（SHGM）的非线性光学成像技术，开发一种新的多模态方法，用于上皮癌前病变和早期肿瘤的光学分期。该研究将结合检测和绘制MPM评估的上皮和基质中内源性组织自身荧光的能力，以及源自基质结构蛋白（主要是胶原蛋白）的二次谐波产生。重要的光学和显微结构改变已被证明与肿瘤转化。然而，尽管许多先前的光学方法对肿瘤变化具有高灵敏度，但它们通常在检测和分期方面缺乏特异性。预计通过MPM-SHGM深入评估微结构和光学变化的能力，导致类似于组织学水平的图像表示，将导致比以前的技术更高的特异性。MPM-SHGM技术将在口腔鳞状细胞癌（发生在适合光学评估技术发展的部位）模型中得到发展和完善，并将在未来适用于各种组织部位的其他上皮肿瘤。简而言之，该项目将包括：a)体内上皮肿瘤转化的时空研究，以便更好地了解MPM-SHGM显示的内源性光信号的变化，并确定可能作为肿瘤进展标记的重要图像参数；b) MPM-SHGM开发和完善一种无创分期方法，该方法可能有助于指导手术切除和监测复发风险患者。c)评估外源性造影剂与MPM-SHGM的联合作用，以揭示指示肿瘤潜力的分子特异性信号改变。本研究解决了上皮性肿瘤分期的一个重要问题。一般来说，需要高度特异性的非侵入性检测方法来辅助上皮性肿瘤的早期分期，因为患者的生存机会与上皮性癌症被检测和治疗的阶段直接相关。口腔癌是世界上第六大最常见的癌症，其五年生存率仅为50-55%，它与显著的局部复发率相关，因此早期发现和分期对患者生存至关重要。尽管发生在易于检查的组织中，但高死亡率和发病率，特别是复发后，表明需要改进口腔肿瘤的检测和分期。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to develop a novel multimodal approach for optical staging of epithelial precancerous lesions and early neoplasms using the nonlinear optical imaging techniques of multiphoton microscopy (MPM) and second harmonic generation microscopy (SHGM). The research will combine the ability to detect and map endogenous tissue autofluorescence in the epithelium and stroma assessed by MPM with second harmonic generation originating specifically from stromal structural proteins, primarily collagen. Significant optical and microstructural alterations have been documented with neoplastic transformation. However, while a number of previous optical methods have been associated with high sensitivity to neoplastic change, they generally lacked specificity in detection and staging. It is anticipated that the ability to assess both microarchitectural and optical changes in-depth by MPM-SHGM, resulting in image representations on a level similar to histology, will result in higher specificity than previous techniques. The MPM-SHGM technique will be developed and refined in a model of oral squamous cell carcinoma (which occurs in a site suited for the development of optical assessment techniques) and will be applicable to other epithelial neoplasms at various tissue sites in the future. In brief, the project will involve the a) the spatiotemporal study of epithelial neoplastic transformation in vivo in order to better understand alterations in endogenous optical signals revealed by MPM-SHGM and to identify significant image-based parameters which may serve as markers of neoplastic progression, b) the development and refinement of a noninvasive staging methodology by MPM-SHGM which may assist in guiding surgical resection and in surveillance of patients at risk for recurrence, and c) evaluation of the combination of exogenous contrast agents with MPM-SHGM to reveal molecular-specific signal alterations indicative of neoplastic potential. This research addresses a significant problem in staging of epithelial neoplasms. There is a need for highly specific noninvasive detection methods to assist in the early staging of epithelial neoplasms in general because the chances of patient survival are directly correlated to the stage at which epithelial cancers are detected and treated. Oral cancer, the 6th most common cancer in the world and one which is associated with a five-year survival rate of only 50-55%, is associated with a significant local recurrence rate for which early detection and staging is of primary importance to patient survival. Despite occurring in a highly accessible tissue for inspection high mortality and morbidity rates, particularly following recurrence, indicate the need for improved detection and staging of oral neoplasia.